The maintenance of genomic integrity is essential for the health of multi-cellular organisms. DNA damage checkpoints constitute a mechanism where cell division is delayed to allow repair of damaged DNA, or if the extent of DNA damage is beyond repair, induce apoptosis. The three major DNA damage-responsive cell cycle checkpoints are the G1/S checkpoint, intra S-phase checkpoint, and the G2/M checkpoint.
In response to DNA damage, eukaryotic cells activate a complex signaling network to arrest the cell cycle and facilitate DNA repair. This signaling network has traditionally been divided into two major protein kinase pathways, one mediated by Ataxia-Telangiectasia mutated (ATM) through Chk2, and the other mediated by Ataxia-Telangiectasia and Rad-3 related (ATR) through Chk1. Some cross-talk exists between the ATM/Chk2 and ATR/Chk1 kinase pathways, particularly when signaling through one pathway is partially or totally deficient. Normally, however the pathways show only partial functional overlap in response to particular forms of DNA damage. The ATM/Chk2 pathway responds primarily to DNA double strand breaks (DSBs), while the ATR/Chk1 pathway is activated by bulky DNA lesions, and following replication fork collapse during S-phase. The tumor suppressor protein p53 is a major downstream effector of these DNA damage kinase pathways. In normal cells, p53-dependent signaling results in G1 arrest, mainly mediated by transcriptional upregulation of p21. In addition, p21 also appears to play a role in sustaining the G2 checkpoint after γ-irradiation. If the DNA damage is extensive, however, then p53-dependent pathways target the damaged cell for apoptotic cell death through both the intrinsic and extrinsic pathways. Most tumor cells show specific disruptions in the p53 pathway, leading to selective loss of the G1 checkpoint. These cells are then entirely dependent on intra-S and G2/M checkpoints to maintain their genomic integrity in response to DNA damage.
In contrast to the DNA damage-specific activation of Chk1 and Chk2, the p38MAPK pathway is a general stress-activated kinase pathway that responds to various cellular stimuli, including cytokines, hyperosmolarity, and UV irradiation. Activity of p38MAPK is important for G2/M checkpoint function in immortalized fibroblasts and HeLa cells following UV exposure. Furthermore, MAPKAP Kinase-2 (MK2) is the critical downstream effector kinase of p38MAPK required for UV-induced cell cycle checkpoints in U2OS cells.
Whether the observed activation of p38 MAPK/MK2 is a direct result of UV-induced DNA lesions, or results instead from other non-genotoxic effects of UV radiation has been unclear. Similarly, whether the p38MAPK/MK2 pathway is an important part of a general cellular response to genotoxic stress has been unclear. There exists a need to better understand this checkpoint and to develop methods and therapies for disease treatment based on this improved understanding.